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Faculty Profile

Kostantin Dobrenis, Ph.D.

Dr. Kostantin Dobrenis
 

Professional Interests

     Our principal interests lie in the therapy of neurologic diseases and in the field of microglial biology. Much of our work is focused on developing rational therapeutic strategies for genetic diseases that affect the central nervous system (CNS) in a global manner, in particular neuronal storage disorders such as Tay-Sachs disease. The goal here is to find ways to effectively replace the missing lysosomal enzyme within cells throughout the CNS. Towards this, our research has been and is directed to satisfying three important conditions necessary for successful treatment. One is to overcome the blood:brain barrier (BBB) and deliver normal enzymes or genes into the CNS parenchyma in a widespread manner. A strategy for this is the use of appropriately specialized cell lines to serve as vectors able to cross the BBB. These lines would upon introduction into circulation target to and enter the CNS via the vasculature, and release macromolecular therapeutic agents locally. We have derived subpopulations of the monocyte/microglial lineage from unique transgenic animals and have found these cells can enter all major regions of the CNS following intravenous injection into normal mice. We are now employing strategies to enhance efficiency of entry and longevity within the brain. Cell lines efficient in circumventing the BBB could prove invaluable towards treatment of a variety of diseases with global CNS involvement for which current delivery modalities are inadequate. The second and related requirement is to provide sufficient levels of normal exogenous enzyme in the extracellular fluid for subsequent uptake by deficient CNS cells. We have shown that normal microglia and our cell lines do secrete lysosomal enzymes and are now investigating how gene overexpression, cytokine modulation and endosomal pathways can be used to enhance secretion. The third condition is to obtain efficient endocytosis of compounds from the interstitial fluid by neurons. We have previously shown that polylysine or penta-mannosyl-phosphate conjugates of b-hexosaminidase (the enzyme deficient in Tay Sachs disease) could enhance neural cell uptake of enzyme. Most effective for neurons was enzyme derivatized with the atoxic fragment of tetanus toxin (TTC). This resulted in 40-fold enhancement of uptake relative to native enzyme and successful degradation of storage compounds in disease neurons.We are now pursuing geneticmodification of enzymes in our cells lines including a fusion gene incorporating neuronal binding fragments and the retrograde trans-synaptic transfer properties of TTC.

 

Selected Publications

Siegel, D.A., Davies, P., Dobrenis, K. and Huang, M.K. (2006) Tomoregulin-2 is found extensively in plaques in Alzheimer’s disease brain. J. Neurochem. 98:34–44.

Narita, K., Choudhury, A., Dobrenis, K., Sharma, D.K., Holicky, E.L., Marks, D.L.,Walkley, S.U., and Pagano, R.E. (2005) Protein transduction of Rab9 in Niemann-Pick C cells reduces cholesterol storage. FASEB J. 19:1558–1560.

Dobrenis, K., Chang, H.Y., Benabou, M., Woodroffe, A., Lee, S., Rozental, R., Spray, D., Scemes, E. (2005) Human and mouse microglia express connexin36, and functional gap junctions are formed between rodentmicroglia and neurons. J. Neurosci. Res. 82:306–315.

Dobrenis, K. (2004) Cell-mediated therapy. In: Lysosomal Disorders of Brain, F. Platt and S.U. Walkley (eds.), Oxford University Press, Oxford, United Kingdom, pp. 339–380.

McGlynn, R., Dobrenis, K. and Walkley, S.U. (2004) Differential subcellular localization of cholesterol, gangliosides and glycosaminoglycans in murine models of mucopolysaccharide storage disorders. J. Comp. Neurol. 480:415–426.

Abrams, C.K., Freidin, M., Bukauskus, F., Dobrenis, K., Bargiello, T.A., Verselis, V.K., Bennett, M.V.L., Chen, L., and Sahenk, Z. (2003) Pathogenesis of X-linked Charcot-Marie-Tooth Disease: Differential effects of two mutations in connexin 32. J. Neurosci. 23:10548–10558.

Zervas, M., Dobrenis, K., and Walkley, S.U. (2001) Neurons in Niemann-Pick disease type C accumulate gangliosides as well as unesterified cholesterol and undergo dendritic and axonal alterations. J. Neuropathol. Exp. Neurol. 60:49–64.

 

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Contact

Albert Einstein College of Medicine
Rose F. Kennedy Center
1410 Pelham Parkway South , Room 618
Bronx, NY 10461

Tel: 718.430.4027
kostantin.dobrenis@einstein.yu.edu

 
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